PROJECT SUMMARY The aggregated evidence suggests that certain taxa of the early-life upper airway microbiome act as gatekeepers to prevent the onset of childhood respiratory diseases, which are a leading cause of morbidity and mortality in the pediatric population. In this context, the results from our prior studies in children and those from multiple animal studies allude to a potential protective effect of nasal colonization with Lactobacillus in infancy on the development of childhood asthma and other atopic diseases. However, this has not been adequately studied in humans. The mechanisms through which nasal colonization with Lactobacillus in infancy could be protective are also largely unknown. Furthermore, there are currently no available interventions to modify the nasal microbiome in infants at risk of upper airway dysbiosis, such as those born by cesarean section. To address these gaps in knowledge, we propose the following specific aims: Aim 1: To examine whether early- life nasal colonization with Lactobacillus is associated with the establishment of a distinct local immune response and the later development of recurrent wheeze, allergic rhinitis, and childhood asthma. Aim 2: To determine the feasibility of a randomized controlled trial (RCT) assessing the utility of vaginal seeding in modifying the early-life nasal microbiome of infants born by cesarean section. To achieve Aim 1, we will conduct a nested cohort study among a group of healthy infants enrolled in an ongoing large, population- based, birth cohort (n=749). To achieve Aim 2, we will conduct a single-center, parallel-arm, blinded, sham- controlled, feasibility RCT in healthy cesarean-born infants (n=40). The purpose of this NIH K23 ? Independent Clinical Trial Required (PA-18-374) proposal is for the candidate to develop expertise in how to study the impact of the early-life upper airway microbiome on childhood respiratory diseases and how to translate findings to the implementation of clinical trials, so he can ultimately emerge as an independent patient-oriented investigator in the primary prevention of childhood asthma. To accomplish this, he will augment his research skills by achieving the proposed specific aims and through a combination of expert mentorship, advanced didactic coursework, hands-on experience in clinical and microbiome research, and other focused career development activities. He will work closely with a multidisciplinary team of mentors with collective expertise in pediatric asthma epidemiology, microbiome research, microbiology and immunology, and the design and conduct of clinical trials. This team also has extensive experience in fostering the development of early-stage investigators, which ?in addition to a strong institutional commitment to the candidate?s research career and an exceptional academic environment? will undoubtedly ensure his continued success.